Background: Inherited (germline) pathogenic and likely pathogenic variants (gPV) in key genes associated with increased risk of prostate cancer (PrCa) now warrant more attentive prostate cancer screening in NCCN guidelines—e.g., BRCA2, HOXB13, ATM, BRCA1, MSH2, MSH6, PMS2, CHEK2 and TP53. In the case of BRCA2 and others, there is association with more aggressive PrCa. Despite this, early detection guidelines lack specific recommendations for carriers of these risk genes. Data from the international IMPACT study of a targeted PrCa screening program used a PSA threshold to biopsy of >3.0ng/mL and supports initiating screening at the age of 40y. However, questions remain, such as optimal PSA threshold for biopsy and management of suspected cancer risk genes. In the PATROL study, we offer a prospective early detection study for people at risk for PrCa due to known or suspected cancer risk genes, which also serves as infrastructure for engaging people at-risk for PrCa wishing to be proactive and as a framework to investigate novel biomarkers of early detection. Methods: PATROL is a multicenter, prospective study for people who are at known or suspected increased risk for PrCa due to carrying a gPV (e.g., BRCA2) to participate in a PrCa early detection study. The primary endpoint is to determine the positive predictive value of predefined age-directed PSA thresholds and prostate-specific imaging for biopsy. Other exploratory endpoints include characterizing clinico-pathologic characteristics of diagnosed PrCa, and understanding the impact of screening on patient-reported outcomes (e.g., anxiety and decisional regret). Biospecimens to be collected include germline DNA, urine, and tumor tissue to evaluate emerging clinical and research biomarkers. Key eligibility includes: people ≥40y who carry a gPV in an eligible gene, who have no prior diagnosis of PrCa, who do not have another active malignancy, and who provide informed consent. Study procedures include annual physical exam, PSA, and imaging per treating physician. In addition, study will collect annual clinical data, blood and urine, archival biopsy tissue, biomarkers (e.g., SelectMDx). Participants will undergo prostate biopsy per protocol recommendations: for any clinical concern, PSA >1.0 ng/mL if <50y; PSA >1.5 ng/mL if 50-59y; PSA >2.0 ng/mL if =/>60y). If PrCa is diagnosed, clinical care will be determined by the participant and their treating physician. If opting for active surveillance, study procedures will continue to be collected annually for 10 yrs or until definitive treatment. If/when opting for definitive treatment, study procedures will continue to be collected for one additional year. Long-term clinical PrCa outcomes will be collected annually until the study closes. Clinical trial information: NCT04472338.